EMA Validates MAA for Repotrectinib in ROS1+ NSCLC and NTRK+ Solid Tumors

January 3, 2024

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The European Medicines Agency has validated its marketing authorization application for repotrectinib in adult patients with ROS1 TKI-naive or -pretreated locally advanced or metastatic non–small cell lung cancer harboring ROS1 fusions, as well as adult and pediatric patients with TKI-naive and pretreated NTRK-positive locally advanced or metastatic solid tumors.

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The European Medicines Agency (EMA) has validated its marketing authorization application (MAA) for repotrectinib (Augtyro) in adult patients with ROS1 TKI-naive or -pretreated locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring ROS1 fusions, as well as adult and pediatric patients with TKI-naive and pretreated NTRK-positive locally advanced or metastatic solid tumors.¹

The MAA was supported by findings from the phase 1/2 TRIDENT-1 (NCT03093116) and the phase 1/2 CARE (NCT04094610) trials, in which the agent elicited meaningful responses that proved to be durable in these patient subsets. Moreover, intracranial responses were also observed in both settings, as well as in those with tumors harboring common resistance mutations.

“The clinical trial results with repotrectinib highlight the potential for this next-generation therapy to become a best-in-class option for patients with tumors harboring ROS1 fusions and a new option for those with NTRKfusion–positive tumors, two groups who each continue to face a high unmet medical need,” Joseph Fiore, executive director and global program lead for repotrectinib at Bristol Myers Squibb, stated in a press release. “Today’s validation by the EMA brings us another step closer to our goal of making this new targeted therapy available to patients in Europe.”

The multicenter, single-arm, open-label, multicohort TRIDENT-1 trial enrolled patients with locally advanced or metastatic NSCLC harboring ROS1 fusions who had measurable disease by RECIST v1.1 criteria and an ECOG performance status of 0 or 1.² If patients had a history of interstitial lung disease (ILD), drug-associated pneumonitis, prolonged QTc interval, or significant, uncontrolled, or active cardiovascular disease, they were excluded. Efficacy was evaluated in those who had at least 8 months of follow-up since their first dose of the agent. Those with symptomatic brain metastases were excluded.

Participants were administered 160 mg of repotrectinib once daily for 2 weeks and then 160 twice daily. Treatment continued until progressive disease or intolerable toxicity.

The major efficacy outcome measures for the trial were overall response rate (ORR) and duration of response (DOR) by blinded independent central review (BICR) assessment and RECIST v1.1 criteria. Intracranial response was also evaluated by BICR and modified RECIST v1.1 criteria.

The efficacy population was comprised of two groups: those who did not have exposure to ROS1 TKIs but who received up to 1 prior line of platinum-based chemotherapy and/or immunotherapy (n = 71) and those who previously received a ROS1 TKI and did not have prior exposure to platinum-based chemotherapy or immunotherapy (n = 56).

In the ROS1 TKI–naive cohort, the median age was 57 years (range, 28-80). Most patients were female (60.6%), Asian (67.6%), were never smokers (63.4%), had a baseline ECOG performance status of 1 (66.2%), metastatic disease (94.4%), and adenocarcinoma (97.2%). Moreover, 28.2% previously received platinum-based chemotherapy and/or immunotherapy for locally advanced or metastatic disease. In the ROS1 TKI–pretreated cohort, 82% received prior crizotinib (Xalkori) and 16% had prior entrectinib (Rozlytrek). The median age was 57 years (range, 33-78). More than half of patients were female (67.9%), never smokers (64.3%), had a baseline ECOG performance status of 1 (67.9%), metastatic disease (98.2%), and adenocarcinoma (94.6%). Additionally, 48.2% of patients were Asian, 44.6% were White, 1.8% were Black or African American, and 1.8% were Hispanic or Latino. In these 2 cohorts, 25.4% and 42.9% had central nervous system metastases by BICR.

In the ROS1 TKI-naive cohort, repotrectinib elicited an ORR of 79% (95% CI, 68%-88%), which comprised a complete response (CR) rate of 6% and a partial response (PR) rate of 73%. The median DOR was 34.1 months (95% CI, 25.6-not evaluable [NE]), with 70% of patients responding for at least 12 months. Seven of the 8 patients who had measurable CNS metastases at baseline experienced intracranial responses.

In the ROS1 TKI–pretreated cohort, the ORR was 38% (95% CI, 25%-52%), which included a 5% CR rate and a 32% PR rate. The median DOR was 14.8 months (95% CI, 7.6-NE), with 48% of patients responding for 12 months or longer. Five of the 12 patients who had baseline measurable CNS metastases achieved intracranial responses.

Those in the safety population (n = 264), 52% were exposed to repotrectinib for 6 months or longer and 27% were exposed for longer than 12 months.

Thirty-three percent of patients experienced serious adverse effects (AEs), and 4.2% of patients experienced fatal AEs. Eight percent of patients experienced AEs that led to permanent discontinuation; these included dyspnea, pneumonitis, and muscular weakness. Dose interruptions and reductions were required for 48% and 35% of patients, respectively.

The most common AEs experienced by at least 10% of patients included dizziness (all-grade, 63%; grade 3 or 4, 1.9%), dysgeusia (48%; 0%), peripheral neuropathy (47%; 1.9%), ataxia (28%; 0.4%), cognitive disorders (23%; 0.8%), headache (19%; 0%), constipation (36%; 0%), nausea (19%; 0.4%), diarrhea (13%; 0.4%), vomiting (10%; 0.8%), dyspnea (30%; 7%), cough (14%; 0%), fatigue (24%; 1.1%), edema (12%; 0.8%), muscular weakness (21%; 1.5%), myalgia (12%; 0.4%), increased weight (14%; 1.9%), and vision disorders (11%; 0%).

The phase 1/2 CARE study enrolled patients with solid tumors harboring ALK, ROS1, and NTRK1-3alterations.³ Patients needed to have measurable disease by RECIST v1.1 criteria, a Lansky or Karnofsky score of 50, a life expectancy of at least 12 weeks, and acceptable hematologic, renal, and hepatic function. Previous cytotoxic chemotherapy and immunotherapy were permitted.

For phase 1, patients needed to be under 12 years of age; in phase 2, patients needed to be between 12 years and 25 years. Phase 2 comprised 3 cohorts: those with TRK TKI–naive, NTRK-positive advanced solid tumors; t hose with TRK TKI-pretreated, NTRK-positive advanced solid tumors; and those with tumors characterized by other ALK, ROS1, or NTRK alterations or fusions without confirmed measurable disease who are not eligible for the other 2 cohorts.

Repotrectinib was given using weight-based dosing for patients under 12 years of age.4 Those between the ages of 12 years and 25 years were given repotrectinib at 160 mg once daily for the first 2 weeks and may increase to 160 mg twice daily thereafter.

The primary outcome measures for the phase 1 portion were to assess the safety and tolerability and to identify the recommended phase 2 dose (RP2D) of the agent in pediatric patients under 12 years. Secondary end points are focused on evaluating repotrectinib’s antitumor activity in the form of ORR, clinical benefit rate (CBR), time to response (TTR), DOR, and intracranial ORR (IC-ORR) in pediatric and adult patients under 25 years.

Data shared at the 53rd Congress of the International Society of Paediatric Oncology had a data cutoff date of August 2, 2021. At this time point, 10 patients received repotrectinib at 2 dose levels.

Eight patients comprised the efficacy population; this include 4 patients naive to TKIs and 4 who were TKI pretreated. In the TKI-naive subset, 1 patient had NTRK-amplified anaplastic ependymoma, 1 had NTRK-positive glioblastoma multiforme or high-grade glioma, 1 had NTRK-positive sarcoma, and 1 had ROS1fusion–positive inflammatory myofibroblastic tumor. In the TKI-pretreated subset, 2 had NTRK-positive glioblastoma multiforme or high-grade glioma, 1 had NTRK-positive mesoblastic nephroma, and 1 had NTRK-positive sarcoma.

Three of the TKI-naive patients experienced CRs with repotrectinib. One of the patients had NTRK-positive glioblastoma multiforme or high-grade glioma previously had tumor resection, whole brain radiation, and received multiagent chemotherapy, experienced a CR and continued to respond for longer than 3.8 months. The other 2 patients who had a CR continued to respond for longer than 7.3 months and longer than 12.1 months, respectively. One of the TKI-pretreated patients achieved stable disease; this patient had NTRKfusion–positive sarcoma.

Ten patients were evaluated for safety and repotrectinib was found to be well tolerated. The most common treatment-emergent toxicities included anemia (n = 5) and fatigue (n = 5). Three of the 5 patients who experienced anemia had a baseline history of the toxicity. Four patients experienced dizziness, which were grade 1 or 2 and did not result in discontinuation.

No patients discontinued repotrectinib for reasons other than disease progression. No patients required dose reductions and no patients experienced dose-limiting toxicities.

Once the pediatric RP2D is identified, patients under 12 years may enroll into phase 2 of the study.¹ Patients between the ages of 12 and 25 years will directly enroll into the phase 2 concurrent with phase 1 enrollment. The second phase of the trial will evaluate the efficacy and antitumor activity of repotrectinib in pediatric and young adult patients. The primary end point of phase 2 is ORR. Secondary endpoints include CBR, TTR, DOR, IC-ORR, progression-free survival (PFS), CNS-PFS (CNS-PFS), and overall survival.

In November 2023, the FDA approved repotrectinib for use in adult patients with locally advanced or metastatic ROS1-positive NSCLC based on TRIDENT-1 data.⁵ Previously, the regulatory agency granted repotrectinib a breakthrough therapy designation for potential use in patients with advanced solid tumors harboring NTRK gene fusions who have progressed following treatment with 1 or 2 TRK TKIs, with or without prior chemotherapy, and who have no satisfactory alternative options.⁶

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